Role of estradiol in women smokers' acute HPA axis hormone response to naltrexone

说明(申请人提供)：endogenousopioidsystemisinvolvedinacuteresponsetonicotineandthedevelopmentand对尼古丁依赖的维持。相应地，一项正在研究的戒烟治疗试验表明，阿片受体拮抗剂--曲曲酮。然而，最近的临床试验检验了adjunctivetreatmentwithnaltrexoneinsmokingcessationhaveyieldedmixedresultsand，的有效性，因此，进一步researchisneeded.Ofpotentialrelevancetotheseclinicaloutcomes，内源性药物系统和nicotinehaveactiononthehypothalamicpituitaryadrenal(HPA)axis，系统的特殊关联withresponsetostress.SmokershaveanacutelyunderresponsiveHPAaxistostressorsor pharmacologicalactivationcomparedtononsmokers.Importantly，这一功能障碍可能与inmaintenanceofaddictionandsusceptibilitytorelapse.NaltrexoneacutelyactivatestheHPAaxisandithas beenpreviouslyhypothesizedthatthisincreaseinHPAaxisactivitymayunderlienaltrexone‘sefficacyfor treatmentofalcoholismandpossiblysmoking.However，在HPAaxisanditsreductionofsmokingbehaviorhasnotbeeninvestigated.Finally，的行为和unexploredsexdifferencesinsmokers’responsetonaltrexone.Womensmokershaveshownmoreacute sensitivitytonaltrexonethanmenintermsofsubjective，水平上的asbetterquitratesinsmokingcessationtrialsusingnaltrexone.Thesereportedsexdifferencesmaybe反应之间存在一定的关系，而fluctuationsinestradiollevelsacrossthemenstrualcyclemayaffecttheamountofavailableopioid在辐射水平上的差异，主要是在人类和女性之间。因此，在女性中，mayaffecttheefficacyofnaltrexone.Thestudiesinthisapplicationaredesignedto testtheeffectsofnaltrexoneontheHPAaxisandsmokingbehaviorinmaleandfemalesmokers，接受和examinehowestradiollevelaffectstheseresponsestonaltrexoneinfemalesmokers.Inordertoexaminethe对womenwillbetestedattwodifferentstagesofthemenstrual cycle:theearlyfollicularphase(thelowestlevelofestradioloccurringduringthemenstrualcycle)andthelate follicularphase(thehighestoccurringlevelofestradiol).Theresultsofthisstudywouldpotentiallyprovide evidenceforestradiollevelasamechanismunderlyingsexdifferencesinresponsetonaltrexoneandmay havetranslationalclinicalimplicationsfortheuseofnaltrexoneinsmokingcessation.的辐射设置的影响可能与HPA的作用有关。 公共卫生相关性：这项拟议的研究涉及公共健康，因为它将调查男性和女性吸烟者对一种正在接受戒烟检查的药物(纳曲酮)的反应有何不同。这项研究的结果可能对女性(或男性)使用纳曲酮的治疗方式有直接影响。

DESCRIPTION (provided by applicant): endogenousopioidsystemisinvolvedinacuteresponsetonicotineandthedevelopmentand maintenanceofnicotinedependence.Accordingly,onedrugbeinginvestigatedforsmokingcessation treatmentisnaltrexone,aopioidreceptorantagonist.However,recentclinicaltrialsexaminingtheefficacyof adjunctivetreatmentwithnaltrexoneinsmokingcessationhaveyieldedmixedresultsand,therefore,further researchisneeded.Ofpotentialrelevancetotheseclinicaloutcomes,boththeendogenousopioidsystemand nicotinehaveactiononthehypothalamicpituitaryadrenal(HPA)axis,asystemthatisprimarilyassociated withresponsetostress.SmokershaveanacutelyunderresponsiveHPAaxistostressorsor pharmacologicalactivationcomparedtononsmokers.Importantly,thisHPAaxisdysfunctionmayplayarole inmaintenanceofaddictionandsusceptibilitytorelapse.NaltrexoneacutelyactivatestheHPAaxisandithas beenpreviouslyhypothesizedthatthisincreaseinHPAaxisactivitymayunderlienaltrexone'sefficacyfor treatmentofalcoholismandpossiblysmoking.However,therelationshipbetweennaltrexone'sactiononthe HPAaxisanditsreductionofsmokingbehaviorhasnotbeeninvestigated.Finally,theremaybeimportant,yet unexploredsexdifferencesinsmokers'responsetonaltrexone.Womensmokershaveshownmoreacute sensitivitytonaltrexonethanmenintermsofsubjective,behavioral,andHPAaxishormonemeasures,aswell asbetterquitratesinsmokingcessationtrialsusingnaltrexone.Thesereportedsexdifferencesmaybe relatedtodifferencesinlevelsofestradiol,thepredominantestrogeninhumans,betweenmenandwomen.In women,fluctuationsinestradiollevelsacrossthemenstrualcyclemayaffecttheamountofavailableopioid receptorsand,therefore,mayaffecttheefficacyofnaltrexone.Thestudiesinthisapplicationaredesignedto testtheeffectsofnaltrexoneontheHPAaxisandsmokingbehaviorinmaleandfemalesmokers,andto examinehowestradiollevelaffectstheseresponsestonaltrexoneinfemalesmokers.Inordertoexaminethe effectofestradiolonresponsetonaltrexone,womenwillbetestedattwodifferentstagesofthemenstrual cycle:theearlyfollicularphase(thelowestlevelofestradioloccurringduringthemenstrualcycle)andthelate follicularphase(thehighestoccurringlevelofestradiol).Theresultsofthisstudywouldpotentiallyprovide evidenceforestradiollevelasamechanismunderlyingsexdifferencesinresponsetonaltrexoneandmay havetranslationalclinicalimplicationsfortheuseofnaltrexoneinsmokingcessation. PUBLIC HEALTH RELEVANCE: The proposed study relates to public health in that it will investigate how men and women smokers may differ in response to a drug (naltrexone) that is being examined for use in smoking cessation. The results of this study may have direct implications in the manner that women (or men) are treated using naltrexone.